Analysis of a mouse germ cell tumor model establishes pluripotency-associated miRNAs as conserved serum biomarkers for germ cell cancer detection
Abstract Malignant testicular germ cells tumors (TGCTs) are the most common solid cancers in young men. Current TGCT diagnostics include conventional serum protein markers, but these lack the sensitivity and specificity to serve as accurate markers across all TGCT subtypes. MicroRNAs (miRNAs) are sm...
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Nature Portfolio
2025-02-01
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| Online Access: | https://doi.org/10.1038/s41598-025-88554-8 |
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| author | Amanda R. Loehr Dennis M. Timmerman Michelle Liu Ad J. M. Gillis Melia Matthews Jordana C. Bloom Peter K. Nicholls David C. Page Andrew D. Miller Leendert H. J. Looijenga Robert S. Weiss |
| author_facet | Amanda R. Loehr Dennis M. Timmerman Michelle Liu Ad J. M. Gillis Melia Matthews Jordana C. Bloom Peter K. Nicholls David C. Page Andrew D. Miller Leendert H. J. Looijenga Robert S. Weiss |
| author_sort | Amanda R. Loehr |
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| description | Abstract Malignant testicular germ cells tumors (TGCTs) are the most common solid cancers in young men. Current TGCT diagnostics include conventional serum protein markers, but these lack the sensitivity and specificity to serve as accurate markers across all TGCT subtypes. MicroRNAs (miRNAs) are small non-coding regulatory RNAs and informative biomarkers for several diseases. In humans, miRNAs of the miR-371-373 cluster are detectable in the serum of patients with malignant TGCTs and outperform existing serum protein markers for both initial diagnosis and subsequent disease monitoring. We previously developed a genetically engineered mouse model featuring malignant mixed TGCTs consisting of pluripotent embryonal carcinoma (EC) and differentiated teratoma that, like the corresponding human malignancies, originate in utero and are highly chemosensitive. Here, we report that miRNAs in the mouse miR-290-295 cluster, homologs of the human miR-371-373 cluster, were detectable in serum from mice with malignant TGCTs but not from tumor-free control mice or mice with benign teratomas. miR-291-293 were expressed and secreted specifically by pluripotent EC cells, and expression was lost following differentiation induced by the drug thioridazine. Notably, miR-291-293 levels were significantly higher in the serum of pregnant dams carrying tumor-bearing fetuses compared to that of control dams. These findings reveal that expression of the miR-290-295 and miR-371-373 clusters in mice and humans, respectively, is a conserved feature of malignant TGCTs, further validating the mouse model as representative of the human disease. These data also highlight the potential of serum miR-371-373 assays to improve patient outcomes through early TGCT detection, possibly even prenatally. |
| format | Article |
| id | doaj-art-539f951f5f314ce3a9b3d73624a4b718 |
| institution | Kabale University |
| issn | 2045-2322 |
| language | English |
| publishDate | 2025-02-01 |
| publisher | Nature Portfolio |
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| series | Scientific Reports |
| spelling | doaj-art-539f951f5f314ce3a9b3d73624a4b7182025-02-09T12:36:23ZengNature PortfolioScientific Reports2045-23222025-02-0115111310.1038/s41598-025-88554-8Analysis of a mouse germ cell tumor model establishes pluripotency-associated miRNAs as conserved serum biomarkers for germ cell cancer detectionAmanda R. Loehr0Dennis M. Timmerman1Michelle Liu2Ad J. M. Gillis3Melia Matthews4Jordana C. Bloom5Peter K. Nicholls6David C. Page7Andrew D. Miller8Leendert H. J. Looijenga9Robert S. Weiss10Department of Biomedical Sciences, Cornell University College of Veterinary MedicinePrincess Máxima Center for Pediatric OncologyDepartment of Biomedical Sciences, Cornell University College of Veterinary MedicinePrincess Máxima Center for Pediatric OncologyDepartment of Biomedical Sciences, Cornell University College of Veterinary MedicineWhitehead InstituteFaculty of Life Sciences, University of BradfordWhitehead InstituteDepartment of Biomedical Sciences, Cornell University College of Veterinary MedicinePrincess Máxima Center for Pediatric OncologyDepartment of Biomedical Sciences, Cornell University College of Veterinary MedicineAbstract Malignant testicular germ cells tumors (TGCTs) are the most common solid cancers in young men. Current TGCT diagnostics include conventional serum protein markers, but these lack the sensitivity and specificity to serve as accurate markers across all TGCT subtypes. MicroRNAs (miRNAs) are small non-coding regulatory RNAs and informative biomarkers for several diseases. In humans, miRNAs of the miR-371-373 cluster are detectable in the serum of patients with malignant TGCTs and outperform existing serum protein markers for both initial diagnosis and subsequent disease monitoring. We previously developed a genetically engineered mouse model featuring malignant mixed TGCTs consisting of pluripotent embryonal carcinoma (EC) and differentiated teratoma that, like the corresponding human malignancies, originate in utero and are highly chemosensitive. Here, we report that miRNAs in the mouse miR-290-295 cluster, homologs of the human miR-371-373 cluster, were detectable in serum from mice with malignant TGCTs but not from tumor-free control mice or mice with benign teratomas. miR-291-293 were expressed and secreted specifically by pluripotent EC cells, and expression was lost following differentiation induced by the drug thioridazine. Notably, miR-291-293 levels were significantly higher in the serum of pregnant dams carrying tumor-bearing fetuses compared to that of control dams. These findings reveal that expression of the miR-290-295 and miR-371-373 clusters in mice and humans, respectively, is a conserved feature of malignant TGCTs, further validating the mouse model as representative of the human disease. These data also highlight the potential of serum miR-371-373 assays to improve patient outcomes through early TGCT detection, possibly even prenatally.https://doi.org/10.1038/s41598-025-88554-8Testicular germ cell tumorMouse modelmicroRNASerum biomarkerPluripotencyCancer stem cell |
| spellingShingle | Amanda R. Loehr Dennis M. Timmerman Michelle Liu Ad J. M. Gillis Melia Matthews Jordana C. Bloom Peter K. Nicholls David C. Page Andrew D. Miller Leendert H. J. Looijenga Robert S. Weiss Analysis of a mouse germ cell tumor model establishes pluripotency-associated miRNAs as conserved serum biomarkers for germ cell cancer detection Scientific Reports Testicular germ cell tumor Mouse model microRNA Serum biomarker Pluripotency Cancer stem cell |
| title | Analysis of a mouse germ cell tumor model establishes pluripotency-associated miRNAs as conserved serum biomarkers for germ cell cancer detection |
| title_full | Analysis of a mouse germ cell tumor model establishes pluripotency-associated miRNAs as conserved serum biomarkers for germ cell cancer detection |
| title_fullStr | Analysis of a mouse germ cell tumor model establishes pluripotency-associated miRNAs as conserved serum biomarkers for germ cell cancer detection |
| title_full_unstemmed | Analysis of a mouse germ cell tumor model establishes pluripotency-associated miRNAs as conserved serum biomarkers for germ cell cancer detection |
| title_short | Analysis of a mouse germ cell tumor model establishes pluripotency-associated miRNAs as conserved serum biomarkers for germ cell cancer detection |
| title_sort | analysis of a mouse germ cell tumor model establishes pluripotency associated mirnas as conserved serum biomarkers for germ cell cancer detection |
| topic | Testicular germ cell tumor Mouse model microRNA Serum biomarker Pluripotency Cancer stem cell |
| url | https://doi.org/10.1038/s41598-025-88554-8 |
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